Anhydrous, free from ethyl alcohol, including ascomycine compositions for local application

FIELD: medicine; pharmacology.

SUBSTANCE: semifirm pharmaceutical compositions for local application include ascomycene in solution of carrier including three-componental admixture of dissolvents, component not less than 40% wt from lump of composition and consisting from: i) C3-8-alkanol and-or C1-8-alkandiol; ii) fat alcohol iii) additional dissolvents chosen from the family, containing:) alkyl ether of alkancarboxylic acid and-or alkyl ether alkandincarboxylic acid and-or a hydrophylic additional component and-or a triglyceride. Besides, the invention concerns application of the specified composition and the method of treatment of inflammatory and hyperproliferative diseases of skin and dermal implications of immunologically mediated diseases.

EFFECT: improvement of penetration of active substance.

9 cl, 7 tbl, 26 ex

 

The present invention relates to pharmaceutical compositions topical application for the treatment of skin diseases, including ascomycin in the form of a single-phase liquid or semi-solid compositions, practically free from ethyl alcohol and water.

Ascomycin, such as ascomycin and its derivatives are compounds of the class FK 506. FK 506 (tacrolimus) is a known macrolide antibiotic, produced by Streptomyces tsukubaensis No. 9993. In addition, he is a powerful immunosuppressant. The structure of FK 506 listed in the 12th edition of the Merck Index (1996) on s in paragraph 9200. Methods of obtaining FK 506 is described in particular in EP 184162.

Currently, numerous derivatives, agonists, antagonists and analogs of FK 506, preserving its basic structure and at least one of its biological properties (e.g., immunological properties). These compounds are described in numerous publications, for example, in EP 184162, EP 315978, EP 323042, EP 423714, EP 427680, EP 465426, EP 474126, WO 91/13889, WO 91/19495, EP 484936, EP 532088, EP 532089, EP 569337, EP 626385 and WO 93/5059. To denote ascomycin and its derivatives, including FK506, it uses the term "ascomycin".

It is known that the use of ascomycin shown, including for the local treatment of inflammatory and hyperproliferative skin diseases and cutaneous manifestations of the immunologic mediated diseases. The condition of the skin to which it is applied therapy, may be different, including the type and extent of the disease, in addition, the skin may be dry or oily. The skin, in addition, may be covered with hair. There is a need in such pharmaceutical compositions, which could be used regardless of the condition of the skin.

It was found that ascomycin can be prepared in the form of pharmaceutical compositions in the form of a single-phase liquid or semi-solid composition for topical application, practically free from ethyl alcohol and water. Such pharmaceutical composition is effective regardless of the condition of the skin, nails, or mucous membranes, easily tolerated, stable, and have an extremely interesting penetrating properties.

They are amazingly effectively maintain and enhance the useful penetrating properties more complex and inhomogeneous formulations, such as water or hydrocarbon emulsions or suspensions, being at the same time especially convenient in terms of ease of administration and ease of adherence to treatment.

Thus, it was found that a significant part of the composition, of at least 40 wt.%, may consist of simple solvents, which allows you to get light in the transparent liquid solutions or semi-solid gelled dissolve the s.

In particular, the invention relates to single-phase liquid or semi-solid pharmaceutical composition for external use, practically free from ethyl alcohol and water, including one ascomycin in solution media, including three-component mixture of solvents in a quantity of at least 40 wt.% calculated on the total weight of the composition, consisting of:

i)3-8alkanol and/or C1-8alcantera;

ii) a fatty alcohol and

iii) additional solvent selected from a range that contains:

a) alkilany ether alkane-carboxylic acids and/or alkilany ether alkane-dicarboxylic acids and/or

b) hydrophilic cocomponent and/or

triglyceride;

and, optional, optional conventional excipients;

hereinafter briefly referred to as "the composition according to the invention".

The advantages presented in the present invention compositions is that they consist of several components that are simple to prepare and is well tolerated by human skin.

Presented in the invention compositions can be, for example, in the form of solution for topical application, aerosol, solution, gel, ointment, preferably in the form of a gel, foam or ointment.

Preferably the use of semi-solid or foam compositions.

Here and in what follows, the word "phase" Osnach the em what is presented in the invention composition is different from the multi-phase, in particular non-two-phase systems, such as creams and emulsions; they can be in any single-phase form, for example, in solution, or aerosol solution, gel, ointment, or, for example, in the form of a liquid component of the foam, where the active ingredient is usually found in the dissolved form.

"Liquid or semi-liquid" means that the invention compositions are essentially solutions in liquid or solidified liquid form.

"Practically free from ethyl alcohol and water" means that no ethyl alcohol or water is not added intentionally as an indispensable part of the invention compositions. However, a small amount of moisture, for example, up to about 1 wt.% water may be present as impurities of the water contained in the applicable fillers, or in cases when the water is part of an active component, such as a hydrate, in particular when using a crystalline form of A (see application WO 99/01458) component A.

Particularly favorable property in the invention compositions is that the components of the above-described three-component mixture of solvents, as dissolving agents, may also have properties that improve penetration, thus the om at the same time helping to keep the simplicity and effectiveness of the formulations. In addition, it was found that solutions can be thickened without appreciable loss of efficiency.

Specific examples of preferred ascomycin are:

- FK506 (tacrolimus);

- 32-[4-(3,5-acid)imidazol-1-ylethoxy]ascomycin (L-733725) (in Example 1, and as the compound of the formula I in WO 97/8182);

- 32-O-(1-hydroskimming-5-yl) ascomycin (L-732531) (Transplantation. 65. [1998], p.10-18, p.18-26, figure 1 on page 11);

- (32-deoxy-32-EPI-N1-tetrazolyl) ascomycin (ABT-281) (J. Invest. Dermatol. 12. [1999]. s-738, illustration 1 on s);

- 33-epichloro-33-desoxycortisol (pimecrolimus), for example {[1E-(1R,3R,4S)]1R,9S,12S,13R,

- 14S,17R,18E,21S,23S,24R,25S,27R}-12-[2-(4-chloro-3-methoxycyclohexyl)-1-methylvinyl]-17-ethyl-1-1,14-dihidroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28,dioxa-4-azatricyclo [22.3.1.0(4,9)]octakis-18-ene-2,3,10,16-tetraen formula I,

shown in example 66A, including EP 427680 (hereinafter referred to as compound A);

- {[1E-(1R,3R,4R)]1R,4S,5R,6S,9R,10E,13S,15S,16R,17S,19S,20S}-9-ethyl-6,16,20-trihydroxy-4-[2-(4-hydroxy-3-methoxycyclohexyl)-1-methylvinyl]-15,17-dimethoxy-5,11,13,19-tetramethyl-3-oxa-22-azatricyclo[18.6.1.0(1,22)]heptagon-10-EN-2,8,21,27-tetraen described as Examples 6d and 71, in particular in EP 569337 (hereinafter called connection);

- {1R,5Z,9S,12S-[1E-(1R,3R,4R)],13R,14S,17R,18E,21S,23S,24R.25S,27R}17-ethyl-1,14-dihydroxy-12-[2-(4-hydroxy-3-methoxycyclohexyl)-1-methylvinyl]-23,25-dimethoxy-13,19,21,27-Tetra-methyl-1,28-dioxa-4-azatricyclo[22.3.1.0(4,9)]achacoso-5,18-diene-2,3,10,16-tetraen, also known as 5,6-dihydroequilin described as Example 8, in particular, in EP 626385 (hereinafter called a connection).

Although, as stated above, the three-component mixture of solvents is not less than 40 wt.% the total mass of the composition, which, therefore, may contain additional conventional components, preferably accounts for more than 40%, for example, from about 55 to almost 100%, preferably from about 80 or about 90 to about 99.95 percent, more preferably from about 95 to about 99.5% of the total mass.

Each of the components i) and ii), independently of the other, preferably up to about 50, more preferably up to about 20, especially preferably up to about 15% of the total mass. In total, they preferably have up to about 60% of the total mass, preferably 40%, more preferably up to about 30% of the total mass.

The proportion of the component (iii) preferably accounts for up to 75%, more preferably up to about 65% of the total weight of the composition, preferably from 30 to 75% of the total weight.

The active agent is from about 0.05 to 10 wt.% from the total mass is presented in the invention compositions, in particular from 0.1 to 6 wt.%, preferably from 1 to 5 wt.% of the total weight of the composition.

Component i)3-8alkanol preferably represents a straight or do is run rich alkanol, for example isopropanol. Component (i), C1-8alcander preferably is a propylene glycol (i.e. 1,2-propandiol), butyleneglycol, 2-ethyl-1,3-hexanediol and hexyleneglycol (i.e. the 2-methyl-2,4-pentanediol), particularly preferred is a propylene glycol or hexyleneglycol.

Preferably ascomycin and the component (i), at least initially presents in the compositions in a weight ratio of about 0.05 to 10:10-60, more preferably in a weight ratio of about 0.5-10:50-60, particularly preferably in a mass ratio of about 1-3:50-60. However, after application of the drug on the skin more volatile components, such as lower alkanols, can evaporate, leaving a supersaturated solution, which may further increase the penetrating ability.

Component (ii) preferably represents mono - or polyunsaturated fatty alcohol, for example, C12-24then there is a C16-18mono - or polyunsaturated fatty alcohol, preferably alerby alcohol or laidlawii alcohol; especially preferred alerby alcohol.

Ascomycin and component ii) is preferably represented in the compositions in a weight ratio of about 0.05 to 10:5 to 90, more preferably in a weight ratio of about 0.5-10:5-50, particularly preferably in a weight ratio of 1-5:10-20.

Components the HT iii) (a) preferably represents alkilany broadcast With 12-24carboxylic acid, more preferably alkilany broadcast With14-16carboxylic acids, for example, isopropyl ester myristic acid, ethyl ester myristic acid, or isopropyl ester of palmitic acid, especially preferred isopropyl esters of myristic or palmitic acid, or alkilany broadcast With2-10alkalicarbonate acid, for example diisopropyl ether, adipic acid or diethyl ether, adipic acid, especially diisopropyl ester of adipic acid.

Component iii) b) preferably is a suitable for pharmaceutical use simple ether diol, such as dipropyleneglycol or diethylene glycol; W alcohol, such as monoethylamine ether of diethylene glycol; simple fluids alcohol or a partial ester of mono - or polyoxyalkylene with low molecular weight, for example tetrahydrofurfuryl alcohol poliatilenglikola (Glycofurol®); monotropy ether of diethylene glycol (TranscutolR); triethylcitrate; N-organic; dimetridazole (i.e. 1,4:3,6-dianhydro-2,5-di-O-methyl-D-glucitol); or propylene carbonate, are particularly preferred dimetridazole.

Component (iii)preferably consists of medium chain triglycerides such as Miglyol 812R.

Presented in the invention compositions can include, apart from the e, and other usual extra fillers; for example, for convenience of use may be preferred thickened solutions, such as semi-solid slurries, or liquid gel or clear gel. To receive them, you can add grease agents (agents that increase the viscosity) in order to increase the viscosity of the compositions.

Suitable lubricating agents are, for example:

- polyacrylic acid, known under the names of carboxypolymethylene, carboxyquinolone, carbomer, or CarbopolR.

- derivatives of cellulose, including, for example, ethyl-, propyl-, methyl-, hydroxypropyl - and hydroxypropylmethylcellulose,

- colloidal silicon dioxide, such as AerosilRfor example Aerosil R972Ror Aerosil 200R,

polyvinyl alcohol,

- beeswax,

- gidrirovannoe castor oil (Cutina HRR),

- polyvinyl pyrrolidone

- polymethylacrylate gums, for example EudispertRor EudragitRand

- solid alcohols with a chain length12-24for example cetyl alcohol and/or stearyl alcohol, commercially available under the names of LorolR16 and LorolR18, manufacturing Henkel, Germany.

It is preferable to use hydroxypropylcellulose, colloidal silicon dioxide, beeswax, gidrirovannoe castor oil, polyvinylpyrrolidone, or udragit R.

Other common fillers include, for example, ointment base, such as mineral hydrocarbons such as liquid paraffin, vaseline or microcrystalline wax. In those cases when it is advisable to use ointment bases, its amount is, for example, from about 0.1 to about 40%, for example, from about 30 to about 40% of the total weight of the composition.

The composition according to the invention, when appropriate, may include appropriate antioxidants, such as equivalent, ascorbyl palmitate, sodium pyrosulphite, butylhydroxyanisole, propyl ester of para-hydroxybenzoic acid, methyl ester of para-hydroxybenzoic acid and tocopherol. Additionally, the addition of preservatives such as benzyl alcohol, parabens, sorbic acid and phenyl alcohol, can prevent the growth of bacteria. In those cases when it is advisable to presence of antioxidants and/or preservatives, the content of each of them is preferably from 0.01 to 2.5 wt.%.

Compositions according to the invention is preferably free of moisturizing substances, except those cases, when using the last expedient, for example, in the preparation of foam formulations and, as mentioned above, practically free from ethyl alcohol and water.

For the treatment of oily or covered ox is Sanam cover skin it is desirable to use low-fat recipes, such as in the following examples 1 to 17, 22 and 23. The lack of fat and a small amount of residue when applied can increase the ease of use, especially in the case of skin, covered with hair.

The components of the compositions according to the invention described in the publication

..Fiedler, Lexikon der Hilfsstoffe für Pharmazie. Kosmetik und angrenzende Gebiete". Editio Cantor Verlag Aulendorf, Aulendorf, fourth edition, enlarged and revised (1996), the content of which is thus incorporated by reference.

Particularly preferred compositions according to the invention, in which ascomycin represents, for example, pimecrolimus, and

component (i) is isopropanol and/or hexyleneglycol;

component ii) is alerby alcohol and

component (iii) is:

a) diisopropyl ether, adipic acid and/or diisopropyl ether myristic acid and/or

b) dimethyl isosorbide and/or

C) medium chain triglycerides;

and, optional, optional conventional excipients;

in particular the compositions shown below in examples 17 to 20 and 23, especially in example 17.

The composition of the invention is shown for use in the treatment of inflammatory and hyperproliferative skin diseases and cutaneous manifestations of immunologically mediated diseases. The terms "skin" and "skin" ledue is to be understood in a broad sense, including diseases, for example, nails and mucous membranes. Examples of immunologically mediated diseases are alopecia areata, psoriasis, atopic dermatitis, contact dermatitis and other eczematous dermatitis, and seborrheic dermatitis, lichen planus, puzyrchatka, bullous pemphigoid, bullous bullosa, urticaria, angioneurotic oedema, vasculitides, erythema, skin acidosis and lupus erythematosus. Examples of skin diseases include dermatomyositis, a simple Leucoderma, simple ichthyosis, sensitivity, cutaneous T-litteraria lymphoma, acne, autoimmune diseases such as chronic rheumatoid arthritis, scleroderma and similar ailments.

The invention additionally includes a composition that is intended, as stated above, for the treatment of inflammatory and hyperproliferative skin diseases and cutaneous manifestations of immunologically mediated diseases.

Additionally, the invention presents a method for the treatment of inflammatory and hyperproliferative skin diseases or cutaneous manifestations of immunologically mediated diseases, which represent the application of the composition according to the invention on the skin of patients needing treatment.

Additionally, the proposed use of the composition according to the invention for the preparation of the physician the patients for the treatment of inflammatory and hyperproliferative skin diseases and cutaneous manifestations of immunologically mediated diseases.

Additionally, the proposed use of the media to facilitate penetration of ascomycin in the skin, nails and mucous membranes of man, as described above.

The composition of the invention can be prepared in the conventional way, by including a component in the pharmaceutical composition. For example, the composition of the invention can be obtained by dissolving ascomycin suitable for pharmaceutical use alcohol, for example, C3-8alkanol,1-8arcangioli, and/or fatty alcohol. In addition, at the appropriate time and in accordance with the conventional methods can be added and other components, for example alkalemia esters alkenylboronic acids, and/or alkalicarbonate esters, and/or more hydrophilic acomponent, triglycerides or optional conventional additional components.

The following examples illustrate the present invention but do not restrict it.

All information provided in this application the percentages indicate the mass ratio (wt.%), if not otherwise stated. The term "stable" means that the separation of the components of the composition when stored at room temperature does not occur for at least three months or more and there is no decomposition of the active agent. Nevertheless, the hen, for example during storage, may have unintended crystallization, and may be present in the invention compositions a small amount of the active ingredient in crystalline form, which should be attributed to the scope of this invention.

Chemical analysis of the active agent was performed using high performance liquid chromatography (HPLC) with reversed phase and ultraviolet registration; λ=210 nm. The limit of measurement was 0.1 wt.%.

In examples 1 through 25 Connection And (pimecrolimus) can be replaced by a Connection; the Connection; tacrolimus; L-733725; L-732531; and ABT-281,

Examples 1 and 2 (solutions) and 3 (single-phase gel)

Prepared with the following composition:

IngredientsAve. 1Ave. 2Ave. 3
Connection1,08,01,0
i) isopropanol49,042,047,0
propylene glycol---
ii) alerby alcohol10,010,010,0
iii) (a) isopropyl ester of myristic

acid
40,040,0
ii) b) dimethyl ether isosorbidwe acid -40,0-
Additional ingredients:--2,0
Hydroxypropylcellulose (lubricating agent)

Compositions presented in examples 1 through 3, a stable.

Examples 4 through 9 (solutions)

Prepared with the following composition:

IngredientsAve. 4Ave. 5Ave. 6Ave. 7Ave. 8Ave. 9
Connection1,01,01,01,01,01,0
i) isopropanol39,039,039,039,039,039,0
hexylen glycol--10,010,010,010,0
ii) alerby alcohol10,010,010,010,010,010,0
iii) (a) isopropyl ester

myristic acid
--40,0---
isopropyl ether

p is limitedbuy acid
---40,0--
diisopropyl ether

adipic acid
-50,0---40,0
iii) b) dimethyl ether

isosorbidwe acid
50,0---40,0-

Compositions presented in examples 4 through 9, a stable.

Examples 10 through 15 (solutions)

Prepared with the following composition:

IngredientsAve. 10Ave. 11Ave. 12Ave. 13PRAve. 15
Connection2,02,00,50,55,02,0
(i) propylene glycol38,038,0----
hexylen glycol--39,539,535,038,0
ii) alerby alcohol10,010,010,010,010,010,0
iii) (a)-- 50,0---
isopropyl ester of myristic acid
isopropyl---50,0--
ester of palmitic acid
diisopropyl-50,0---50,0
ester of adipic acid
iii) b) dimethyl50,0--50,0-
ether isosorbidwe acid-

Compositions presented in Examples 10 through 15 of the stable.

Examples 16 and 17 (solutions)

Prepared with the following composition:

tr>
IngredientsAve. 16. 17
Connection1,01,0
i) isopropanol-10,0
hexylen glycol5,05,0
ii) alerby alcohol10,010,0
iii) a) diisopropyl ether, adipic acid84,074,0

Compositions presented in examples 16 and 17 stable.

Examples 18 through 21 (semi-solid ointment)

Prepared with the following composition:

IngredientsAve. 18Ave. 19Ave. 20PR*
Connection1,01,01,00,3
i) isopropanol10,010,010,0-
hexylen glycol5,05,05,010,0
ii) alerby alcohol10,010,010,010,0
iii) a) diisopropyl ether

adipic acid
32,054,064,0-
iii) triglycerides with medium length

chain (Miglyol 812)
---440
Additional ingredients:--
liquid paraffin (wax base)32,029,7
Colloidal silicon dioxide (Aerosil10,0--6,0
R972) (lubricating agent)
Beeswax (lubricating agent)-20,0--
Gidrirovannoe castor oil

(Cutina HR) (lubricating agent)
--10,0-
* oleogel

Compositions presented in examples 18 through 21 stable.

Examples 22 to 25 (solutions)

Prepared with the following composition:

hexylen glycol
IngredientsAve. 22Ave. 23Ave. 24Ave. 25
Connection0,84,00,60,2
i) isopropanol10,010,010,0-
5,05,010,010,0
ii) alerby alcohol10,010,010,010,0
iii) (a) isopropyl ester

myristic acid
---49,8
diisopropyl ether adipic

acid
-71,0--
iii) medium chain triglycerides (Miglyol 812)74,2-39,4-
Additional ingredients: liquid paraffin (wax base)--30,030,0

Compositions presented in examples 22 to 25, a stable.

The usefulness of the compositions according to the invention can be observed in standard clinical tests such as the following test, using the concentration of the active agent is 0.005 to 10 wt.% (preferably 0.1 to 3 wt.%).

Representative clinical trial was performed in the following way:

Randomized, double-blind, controlled in relation to the media, with comparisons performed in the same patients, a study that compared presented in the invention composition in to the iruke active agent, from 0.1 to 3 wt.% (based on the total weight of the composition) to the affected skin area, for example, 200 cm2that corresponds to 0.5 to 50 mg of the composition per square centimeter, preferably from 1 to 10 mg of the composition per square centimeter, with the application of placebo on the affected skin area as a positive control, was conducted on patients suffering from inflammatory and hyperproliferative skin diseases or cutaneous manifestations of immunologically mediated diseases.

The affected skin of patients were treated with the specified composition twice daily for six months. Evaluated therapeutic effect, the effectiveness was determined on the basis of the time required for partial purification. Registered local tolerability of the investigational drug and the standard security settings, including hematological and clinical chemistry.

Usefulness can also be observed in the tests carried out on young domestic pigs, which was experimentally induced allergic contact dermatitis (J.Investig. DermatoL, 98, [1992], s-855). Several formulations were examined for suppression of inflammatory changes (redness and infiltration) through clinical studies. Effectiveness was determined on the basis of comparison of inflammatory changes in treated and untreated areas of skin which are located on opposed the s sides of the same animal. The results are shown below:

The formulation according to example No.Efficiency compared with untreated plots (average %; n=12**)
1679
1773
1878
2060
1% pimecrolimus cream68
** each formulation was tested at 2 sites in 6 animals

The exact amount of the compositions according to the invention needed for the application depends on various factors, such as the desired duration of treatment, and the speed of release of the active agent. In larger mammals, for example humans, satisfactory results are obtained when the local application on the area treated active agent in a concentration of from 0.05 to 10 wt.%, preferably from 0.1 to 3%, several times a day (for example, from 2 to 5 times a day). In General, the composition can be applied to the skin area from just 1 cm20.5 m2preferably the composition should be applied to areas of the scalp, in the treatment of inflammatory and hyperproliferative skin diseases or kovnik manifestations of immunologically mediated diseases. Priemlemaya load active agent comprise 0.005 cm 2. up to 1 cm2.

Discovered that is provided in the invention composition is effective regardless of the condition of the skin and is well tolerated by the skin. They are easy to apply on large areas of skin, using conventional methods of application, for example, a brush, a cotton swab thread, in the form of aerosols for topical application, or a roll-on applicator. Thus, they are very easy to use.

1. Single-phase liquid or semi-solid pharmaceutical composition for topical application intended for the treatment of inflammatory and hyperproliferative skin diseases and cutaneous manifestations of immunologically mediated diseases, practically free from ethyl alcohol and water, which includes ascomycin in solution media, including three-component mixture of solvents, which is not less than 40 wt.% of the total weight of the composition and consists of:

i)3-8alkanol and/or C1-8alcantera;

ii) a fatty alcohol; and

iii) additional solvent selected from the set consisting of:

a) Olkiluoto ether alkenylboronic acid and/or alkylboron ether alkalicarbonate acid, and/or

b) hydrophilic acomponent, such as a simple ether diol fluids alcohol, simple fluids alcohol or a partial ester of mono - or polyoxyalkylene low mole is Blarney mass, monotropy ether of diethylene glycol, triethylcitrate; N is an organic, dimetridazole or propylene carbonate, and/or

in) triglycerides;

and, optionally, additional conventional fillers.

2. The composition according to claim 1, in which ascomycin represents pimecrolimus.

3. Composition according to claims 1 and 2, in which:

component i) is isopropanol and/or hexyleneglycol;

component ii) is alerby alcohol; and

component (iii) is:

a) diisopropyl ether, adipic acid and/or isopropyl ester of myristic acid, and/or

b) dimethyl isosorbide, and/or

in) triglycerides medium chain length;

and, optionally, additional conventional fillers.

4. The composition according to claim 1 or 2, additionally comprising conventional fillers, selected from a range that contains hydroxypropylcellulose, liquid paraffin, colloidal silicon oxide, beeswax and gidrirovannoe castor oil.

5. The composition according to claim 1 or 2, in which the number of ascomycin is from 1 to 5% by weight of the total composition.

6. The composition according to claim 1 or 2 in the form of a gel, foam or ointment.

7. The method of treatment of inflammatory and hyperproliferative skin diseases and cutaneous manifestations of immunologically mediated diseases, on the expectation by applying to skin in need of such treatment compositions according to claim 1 or 2.

8. The use of compositions according to claim 1 or 2 for the preparation of drugs for the treatment of inflammatory and hyperproliferative skin diseases and cutaneous manifestations of immunologically mediated diseases.

9. The use of media, including three-component mixture of rastvoritelei, consisting of:

i)3-8alkanol and/or C1-8alcantera;

ii) a fatty alcohol; and

iii) additional solvent selected from the set consisting of:

a) Olkiluoto ether alkenylboronic acid and/or alkylboron ether alkalicarbonate acid, and/or

b) hydrophilic acomponent, such as a simple ether diol fluids alcohol, simple fluids alcohol or a partial ester of mono - or polyoxyalkylene with low molecular weight, monotropy ether of diethylene glycol, triethylcitrate; N is an organic, dimetridazole or propylene carbonate, and/or

in) triglycerides;

to enhance the penetration of ascomycin in the skin, the nails or mucous membranes of a person.



 

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11 cl, 16 dwg, 11 ex, 6 tbl

FIELD: medicine; pharmacology.

SUBSTANCE: variants of the combined protein which contain the extracellular domain of a human receptor of a hormone of growth and the domain which includes alarm sequence for joining glycosylphosphatidylynozyte (GPI) anchors are offered.

EFFECT: effective medical product for acromegalia and gigantism treatment.

8 cl, 16 dwg

FIELD: medicine.

SUBSTANCE: for treatment of atopic dermatitis, use the autologous T-lymphocytes, activated with the help of anti CD3 antibodies and interleukin-2. The activated T-lymphocytes are administered subcutaneously once a week within 4 weeks and further once a month within one year. Simultaneously perform basic therapy by antihistamine preparations and topical glucocorticosteroids.

EFFECT: depression of clinical implications of disease at the expense of influence on the changed immune response through an induction of the antiergotypical response.

2 ex

FIELD: medicine; pediatrics.

SUBSTANCE: administer arbidol in a dose of 50 mg 2 times a week in a combination with active selenium in a dose of 25 mkg on selenium once a day. Duration of prevention - 3-4 weeks.

EFFECT: reduction of frequency and general duration of respiratory infections at the expense of simultaneous correction of disturbances of the immune and metabolic status.

2 tbl, 3 ex

FIELD: chemistry, immunology.

SUBSTANCE: extraction of dried cook water of sea cucumber Cucumaria frondosa or dried powder tissues of Cucumaria frondosa by chloroform and methanol mix is performed during boiling with reflux condenser to obtain organic extract; extract is evaporated, evaporated extract is re-dissolved in water, obtained colloid solution is decanted, ethylacetate is added to solution, water phase is decanted and undergoes chromatography in teflon or silica gel columns. Immune system activity of mammals, including lizosomic activity, phagocitosis and active oxygen form generation in macrophags of mammals, infected with bacterial cells, viruses and protozoa, is stimulated by oral, intraperitoneal or intramuscular or combined introduction of frondosite A dosage of 1 to 15 mcg/kg, preferably 10 mcg/kg.

EFFECT: implementation of claimed objective.

11 cl, 18 ex

FIELD: medicine; pharmacology.

SUBSTANCE: apply the compound chosen from the group consisting of N-benzil-N'-(2,6-diisopropylphenyl)-N-isopropylmalonamide, N'-[2,6-bis(1-methylethyl)phenyl]-N-(1-methylethyl)-N-[[4(methylthio)phenyl]methyl]propandiamide and N-[2,6-bis(1-methylethyl)phenyl]-[β-[[(4-methoxyphenyl)methyl](2-pyridinil)amino]]-β-oxopropanamide.

EFFECT: obtaining of a medical product for fat skin, reduction of secretion of skin fat and a pharmaceutical composition for local application on their basis.

9 cl, 3 tbl, 1 ex

FIELD: medicine; pharmacology.

SUBSTANCE: apply the compound chosen from the group consisting of N-benzil-N'-(2,6-diisopropylphenyl)-N-isopropylmalonamide, N'-[2,6-bis(1-methylethyl)phenyl]-N-(1-methylethyl)-N-[[4(methylthio)phenyl]methyl]propandiamide and N-[2,6-bis(1-methylethyl)phenyl]-[β-[[(4-methoxyphenyl)methyl](2-pyridinil)amino]]-β-oxopropanamide.

EFFECT: obtaining of a medical product for fat skin, reduction of secretion of skin fat and a pharmaceutical composition for local application on their basis.

9 cl, 3 tbl, 1 ex

FIELD: chemistry, pharmacology.

SUBSTANCE: claimed invention relates to water-free crystalline form 6-[[(3S,4R)-3,4-dihydro-3-hydroxi-6-[(3-hydroxiphenyl)sulfonyl]-2,2,3-trimethyl-2H-1-benzopyrane-4-yl]oxy]-2-methyl-3(2H)-pyridasinon, whose powder radiograph is in fact similar to radiograph, presented in Figure I, and on which there is at least one characteristic pinnacle with approximate values 2θ, selected from group, which consists of 10.5°, 15.0°, 17.2° and 22.8°, a well as to method of obtaining it and method of hair growing stimulation by introducing composition which is based on said crystalline form into mammal.

EFFECT: obtaining effective means, which stimulate hair growing.

9 cl, 8 dwg, 4 ex

FIELD: medicine.

SUBSTANCE: means include biopolymer carrier and cells, applied on carrier mentioned, and characterised as follows: the biopolymer carrier represents collagen-chitosan film, or crumbs of collagen-chitosan film, or high polymer gel in form of 5% macrogol-1500 solution; the cells are diploid human lung strain "ФЭЧ" 16-1 cells, or diploid human musculo-cutaneous tissue strain "ФЭЧ" 16-2 cells in concentration 2.0-3.0×105 to 1 cm2 of film or crumb carrier, or 1.0×106 to 1 ml carrier in form of 5% macrogol solution high polymer gel.

EFFECT: novel means production for replacement therapy based on standard certified cell material, possibility of optimal means form selection, reducing therapy duration, and widening field of application in replacement therapy.

3 cl, 17 ex, 3 tbl

FIELD: medicine.

SUBSTANCE: preparation represents mix of calendula flowers oil extract, cottonweed herb, camomile flowers, dog-rose seeds, and St. John's wort herb, taken in proportion as follows, in g to 3.0 l unrefined sunflower oil: calendula (flowers) 100.0, cottonweed (herb) 100.0, camomile (flowers) 100.0, St. John's wort (herb) 150.0, dog-rose (seeds) 35.0, unrefined sunflower oil 3.0 l; and 40% alcohol solution, containing 0.5% Novocain injection solution, 50% analgin injection solution, 70% calendula tincture, aloe juice, menthol powder, anesthesin powder, taken in proportion as follows, in ml: 0.5% Novocain injection solution 25.0, 50% analgin injection solution 10.0, 70% calendula tincture 20.0, aloe juice 25.0, menthol (powder) 12.0 g, anesthesin (powder) 12.0 g, 40% alcohol solution 500.0; 8.0 ml of the oil extract being added to 40% alcohol solution.

EFFECT: quickened wound epithelisation, quickened necrotic tissues rejection, shortened wound repair period, and stimulation of new granulation tissue development with rapid maturation.

3 ex

FIELD: medicine; dermatology.

SUBSTANCE: preliminary wound sanitization by 2-5% aqueous argovit solution is carried out. Then silver electrophoresis is performed with the use as anode of padding polyester stripes modified by silver. After that a dressing by 2-5% argogel is carried out.

EFFECT: effective treatment due to antibacterial influence prolongation and trophicity improvement in damage zone.

5 ex

FIELD: chemistry.

SUBSTANCE: novel compounds of formulas , , , , , , (designation of all groups are given in invention formula) are used for treatment of different metabolic diseases, such as insulin resistance syndrome, diabetes, hyperlipidemia, fatty liver, cachexia, obesity, atherosclerosis and arteriosclerosis.

EFFECT: using compounds as biologically active agent and creating pharmaceutical compositions based on said compounds.

124 cl, 52 ex, 17 tbl, 2 dwg

FIELD: medicine.

SUBSTANCE: according to invention, agent includes silicon composition of high laying viscosity becoming firm when applied through cross-link to form skin-favourable elastomer adhesive to skin. Invention also refers to method of agent application.

EFFECT: provision of protection of circumwound cutaneous covering.

15 cl, 4 dwg

FIELD: medicine.

SUBSTANCE: tablets Iodantirypine are taken in dose 100 mg twice a day within 30 days. Simultaneously suppositories genferon are used in dosage 250000 ME vaginally for women and in dosage 500000 ME through rectum for men. Suppositories are introduced twice a day within 10 days. In case condyloma sizes within 0,1 to 1 cm, specified pharmacotherapy is simultaneously combined with chemical destruction thereof.

EFFECT: provides complex antiviral, antiinflammatory, regenerating, anti-oxidant, membrane stabilising action, reduced recurrence rate without by-effects.

2 ex

FIELD: medicine.

SUBSTANCE: 7-30 days prior to ultra-violet solar radiation (UVSR) exposure patient is introduced with effective amount of composition containing natural lykopin, and one or more carotinoids chosen of phytoene, phytofluene or their mixtures. The specified composition can be used in the form of oral dosed form containing 5 to 15 mg natural lykopin, 0.5 mg to 3.5 mg phytoene and/or phytofluene, 1.5 to 8 mg vitamin E. The specified composition is introduced as pharmaceutical preparation, food or drink.

EFFECT: provide improved component bioavailability and synergism concerning skin protection from UVSR at safe application.

9 cl, 1 dwg, 2 ex

FIELD: medicine; pharmacology.

SUBSTANCE: water pharmaceutical solution contains oxymetazoline and/or xylomethazolinum, salt of zinc and buffer salt and its applications for local introduction in nose for putting off of edema of mucosa.

EFFECT: increased stability, reduction of hydrolysis of active substances in the presence of zinc salt.

17 cl, 8 ex, 1 tbl

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